[A case of thrombotic microangiopathy with glomerular subendothelial IgA deposition due to bevacizumab].

Bevacizumab, an inhibitor of vascular endothelial growth factor, is approved for the treatment of various cancers, but the incidence of proteinuria as a side effect has been reported to be 2-64%. We report a case of renal impairment due to thrombotic microangiopathy (TMA) accompanied with glomerular subendothelial deposition of IgA resulting from bevacizumab administration. A 57-year-old female with advanced breast cancer, to whom bevacizumab had been administered from October 2012, developed proteinuria and epithelial casts in her urine about a month later. Serum creatinine remained at 0.7-0.8 mg/dL until June 2013, but gradually increased to 1.3 mg/dL in September. She was referred to our hospital because her renal function had not improved despite termination of bevacizumab, and a renal biopsy was performed in October. At that time, the levels of proteinuria, serum creatinine and serum IgA were high at 1.3 g/g x Cr, 1.6 mg/dL and 430 mg/dL, respectively. Histological examinations showed prominent IgA deposits in the subendothelial area and glomerular infiltration of CD68 positive cells in addition to features of TMA, such as narrowed glomerular capillary lumina and double contours of the basement membranes. In consideration of her clinical history, a diagnosis of bevacizumab-induced TMA was made. Through follow-up care without readministration of bevacizumab, epithelial casts in her urine disappeared, and proteinuria decreased to 0.62 g/g x Cr in November. Serum creatinine remains high at around 1.3 mg/dL, but has not elevated further. Serum IgA gradually decreased and reached 289 mg/dL in April 2014. TMA due to bevacizumab described in several other reports was also accompanied by glomerular IgA deposition, thus a differential diagnosis of IgA nephropathy is required. TMA was recently added to a section of "significant adverse effects" in the package insert of bevacizumab. Nephrologists should be fully aware of this drug-induced nephropathy.

Serial changes in adipocytokines and cardiac function in a rat model of the metabolic syndrome.

Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr-cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar-Kyoto rats. We also assessed age-related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor-α and interleukin-6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week-old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome.

Evaluation of estimated creatinine clearance before steady state in acute kidney injury by creatinine kinetics.

BACKGROUND: A simple method to calculate estimated creatinine clearance using two serum creatinine concentration (Cr) values in acute kidney injury (AKI) was developed (eCrCl-AKI). We aimed to evaluate its accuracy and to clarify its contribution to the classification of AKI. METHODS: We validated the errors in eCrCl-AKI in a simulation study after various reductions in creatinine clearance (CrCl) at various levels of chronic kidney disease (CKD). We compared the eCrCl-AKI-based classification of RIFLE criteria with the Cr-based classification or that proposed by Waikar and Bonventre. The regression equations of eCrCl-AKI on time were determined and Cr values were reconstructed by creatinine kinetics substituting CrCl with eCrCl-AKI in actual patients. RESULTS: Most errors in eCrCl-AKI were relatively small (from -13.6 to +7.9%) with the exception of two Cr values that straddled the changing trend of Cr. The classification according to RIFLE criteria based on Cr was unstable and did not enable adequate classification, especially in milder reductions of CrCl with advanced CKD. The classification based on eCrCl-AKI was stable and enabled adequate classification. There were good agreements between measured Cr and reconstructed Cr with eCrCl-AKI. The regression equations of eCrCl-AKI revealed changes of renal function that were unexpected only from fluctuations of Cr. CONCLUSIONS: eCrCl-AKI can provide relatively accurate estimates for fluctuating CrCl. eCrCl-AKI enables more stable and earlier classification of AKI than Cr, at least in the simulation study. The more widespread use of eCrCl-AKI in actual clinical settings of AKI is necessary to evaluate this formula.

Differentiation and isolation of iPSC-derived remodeling ductal plate-like cells by use of an AQP1-GFP reporter human iPSC line.

Cholangiocytes are the epithelial cells that line bile ducts, and ductal plate malformation is a developmental anomaly of bile ducts that causes severe congenital biliary disorders. However, because of a lack of specific marker genes, methods for the stepwise differentiation and isolation of human induced pluripotent stem cell (hiPSC)-derived cholangiocyte progenitors at ductal plate stages have not been established. We herein generated an AQP1-GFP reporter hiPSC line and developed a combination treatment with transforming growth factor (TGF) ß2 and epidermal growth factor (EGF) to induce hiPSC-derived hepatoblasts into AQP1+ cells in vitro. By confirming that the isolated AQP1+ cells showed similar gene expression patterns to cholangiocyte progenitors at the remodeling ductal plate stage around gestational week (GW) 20, we established a differentiation protocol from hiPSCs through SOX9+CK19+AQP1- ductal plate-like cells into SOX9+CK19+AQP1+ remodeling ductal plate-like cells. We further generated 3D bile duct-like structures from the induced ductal plate-like cells. These results suggest that AQP1 is a useful marker for the generation of remodeling ductal plate cells from hiPSCs. Our methods may contribute to elucidating the differentiation mechanisms of ductal plate cells and the pathogenesis of ductal plate malformation.

Patient-Specific Relationship Between Hydraulic Permeability of Microvasculature and the Extent of Burden of Excess Fluid in Hemodialysis Patients.

We have reported a significant correlation between hydraulic permeability of microvasculature adjusted with ultrafiltration rate (AdjLpst) and excess fluid divided by dry weight (ExF/DW) in a cross-sectional study of hemodialysis patients. We aimed to study longitudinally whether a similar relationship between them exists in each patient. Twelve hemodialysis (HD) patients in whom AdjLpst and ExF/DW had been measured more than four times (total of 85 measurements) were enrolled. AdjLpst was calculated by monitoring blood volume during HD. ExF was calculated from the fluid volume measured via bioimpedance spectroscopy. The borders of overhydration were 1.66 mL/mm Hg per min for AdjLpst and a positive value for ExF/DW. There was a significant correlation between AdjLpst and ExF/DW (r = 0.517). When the 85 measurements were classified into four quadrants according to ExF/DW and AdjLpst, the evaluations of fluid status agreed in 66 measurements. In six patients, significant positive correlations were found. In nine patients, equal to or more than 80.0% of evaluations by AdjLpst and those by ExF/DW agreed. In only one patient was there neither significant correlation nor agreement. AdjLpst of two patients suffering from chronic heart failure and microscopic polyangiitis was reduced compared with that of others loaded with the same extent of excess fluid. We concluded that there was a significant correlation between AdjLpst and ExF/DW and high agreement between evaluation by AdjLpst and evaluation by ExF/DW in the majority of patients. However, the relationship between them was patient-specific to some extent.

The evaluation of filtration coefficients of microvasculature for the assessment of fluid status in hemodialysis patients.

PURPOSE: Bioimpedance spectroscopy (BIS) is widely used to assess fluid status in hemodialysis (HD) patients. Our purpose is to evaluate filtration coefficients (Lpst) as an alternative test to assess fluid status by utilizing BIS as a reference test.
 METHODS: 106 HD patients (determined group) were divided into two groups with (EX group: 53) or without excess fluid mass (ExF). ExF calculated from extracellular water and intracellular water measured by BIS. Multiple linear regression equation of Lpst was made using ExF (ExF/DW) and ultrafiltration rate (UFR/DW) to adjust Lpst (AdjLpst). The cut-off values of the tests for detection of EX were determined by receiver-operator characteristic curve analysis. Lpst, AdjLpst, serum atrial natriuretic peptide concentration (ANP), ultrasonically measured inferior vena cava diameter (IVCe/BSA), and blood volume change (Δ BV/TUF/DW) were examined. The detection abilities of these tests were evaluated in the distinct 61 patients (evaluated group).
 RESULTS: Patients of the EX group numbered 29 in the evaluated group. The correlation between AdjLpst and ExF/DW was the highest. The sensitivity of AdjLpst and specificity of Lpst were the highest. The specificity of AdjLpst was equivalent to that of Lpst. Unadjusted and adjusted odds ratios of AdjLpst were the higher (20.80, 95% CI, 5.61-77.10, 16.06, 95% CI 4.00-64.59, respectively) than those of the other tests.
 CONCLUSIONS: AdjLpst can detect patients of the EX group more accurately than other tests. Because AdjLpst is related to plasma refilling, it may indicate removable fluid overload. AdjLpst in conjunction with BIS may contribute to more adequate fluid management.